Compound having bruton&#39;s tyrosine kinase (btk)-inhibition and degradation activity

ABSTRACT

A compound for inhibiting and degrading Bruton&#39;s tyrosine kinase (Btk) is disclosed. The compound is a substituted glutarimide represented by Formula I′. The compound can be used in the preparation of drugs for treating Btk activity-related diseases.

TECHNICAL FIELD

The present invention belongs to the field of medicine, and particularlyrelates to a class of compounds having the activity of degradingtyrosine protein kinase Btk, and preparation and application thereof.

BACKGROUND

Btk, i.e. Bruton's tyrosine kinase, is a member of the Tec family ofnon-receptor tyrosine kinases. It is an essential gene for celldifferentiation and proliferation, and is expressed in B-cell lymphoma,acute lymphoblastic leukemia (ALL) and plasmacytoma. Btk is a keycomponent of the B cell receptor (BCR) signaling pathway and is a goodsite for targeted treatment of diseases such as B-cell lymphoma.

Btk is a key regulator of B cell development, activation, signaling andsurvival, and is involved in the regulation of angiogenesis, cellproliferation and apoptosis, and cell movement. In addition, Btk is alsoinvolved in many other hematopoietic cell signaling pathways, such asparticipating in Toll-like receptors and cytokine receptor mediatedsignaling pathways in macrophages, and participating in IgE receptorsignaling in mast cells.

Recent studies have shown that Btk signaling pathway is a new hotspotcurrently in clinical treatment research for non-Hodgkin's lymphoma(NHL), especially chronic lymphocytic leukemia (CLL), B-cell lymphomaand autoimmune diseases (rheumatoid arthritis, psoriasis, etc.) (DengRong, Zhao Lizhi. Research progress of Btk inhibitors. PharmaceuticalResearch, 2014, 33 (6): 359-372).

Therefore, those skilled in the art are committed to developingcompounds capable of inhibiting Btk activity.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound capable ofinhibiting and degrading Btk, and preparation and application thereof.

In the first aspect of the present invention, there is provided acompound represented by the following formula I, or a pharmaceuticallyacceptable salt thereof:

wherein,

— refers to a single bond;

refers to a single or double bond;

A is missing or selected from C(═O), C(═O)X1, SOX1, SO₂X1, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), and C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s); wherein XI is missingor selected from (CR₁₂R₁₃)_(j)O, (CR₁₂R₁₃)_(j), 3- to 8-memberedheteroaromatic ring (preferably, such as pyridyl, or 1,2,3-triazolyl)with or without substituent(s), 3- to 8-membered aromatic ring(preferably, such as phenyl) with or without substituent(s), and NR₁₄;wherein R₁₂, R₁₃, R₁₄ is each independently H, C₁₋₈ hydrocarbyl groupwith or without substituent(s), C₁₋₈ cyclic hydrocarbyl group with orwithout substituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with orwithout substituent(s); j is an integer between 0 and 3;

W is missing or selected from O, NR₁₇, —X2C(═O)X3, —X2S(═O)_(g)X3;wherein R₁₇ is independently H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s); wherein X2, X3 is each independently missing or selectedfrom O, S, and NR₁₈; wherein g is an integer between 0 and 2; whereinR₁₈ is independently H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Y is (CR₂₂R₂₃)_(h), CHX4(CR₂₂R₂₃)_(h), CX4═CH(CR₂₂R₂₃)_(h),C(═CH₂)(CR₂₂R₂₃)_(h) or (CR₂₂R₂₃)_(h); wherein h is an integer between 0and 30; wherein R₂₂, R₂₃ is each independently H, cyano, hydroxyl,amino, C₁₋₈ hydrocarbyl group with or without substituent(s), C₁₋₈cyclic hydrocarbyl group with or without substituent(s), C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s), or C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X4 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Z is (CR₂₄R₂₅)_(i), CHX5(CR₂₄R₂₅)_(i), CX5═CH(CR₂₄R₂₅)_(i) orC≡C(CR₂₄R₂₅)_(i); wherein i is an integer between 0 and 30; wherein R₂₄,R₂₅ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X5 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

B is missing or selected from O, C═O, S, NR₁₅, —NR₁₅C(═O)—, —C(═O)NR₁₅—,—C(═O)O—, OC(═O)O—, —NR₁₅C(═O)O—, —OC(═O)NR₁₅—, —NR₁₅C(═O)NR₁₆—, C₁₋₁₂hydrocarbyl group with or without substituent(s), C₁₋₁₂ cyclichydrocarbyl group with or without substituent(s), and C₁₋₁₂ heterocyclichydrocarbyl group with or without substituent(s); wherein R₁₅, R₁₆ iseach independently selected from H, C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

X is selected from CR₁₉R₂₀, C(═O), S(═O), SO₂, and NR₂₁; wherein R₁₉,R₂₀ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), or C₁₋₈ hydrocarbyloxygroup with or without substituent(s); wherein R₂₁ is selected from H,C₁₋₈ hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), and C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

R₁ is selected from H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), cyclic hydrocarbyl group with or without substituent(s),heterocyclic hydrocarbyl group with or without substituent(s) and C₁₋₆acyl group with or without substituent(s);

R₂, R₅ is each independently selected from H, OR₃₃, NR₃₄R₃₅, cyano,halogen, C₁₋₈ hydrocarbyl group with or without substituent(s), cyclichydrocarbyl group with or without substituent(s), heterocyclichydrocarbyl group with or without substituent(s), C₁₋₆ acyl group withor without substituent(s) and amido group with or withoutsubstituent(s); wherein R₃₃, R₃₄, R₃₅ is each independently selectedfrom H, C₁₋₈ hydrocarbyl group with or without substituent(s), cyclichydrocarbyl group with or without substituent(s), and heterocyclichydrocarbyl group with or without substituent(s);

R₃, R₆, R₇, R₈, R₉, R₁₀, R₁₁ is each independently selected from H,OR₂₇, NR₂₈R₂₉, cyano, halogen, nitro, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), heterocyclic hydrocarbyl group with or withoutsubstituent(s), X6S(═O)_(k)R₃₀, X6C(═O)R₃₁; wherein k is 0 to 2; whereinR₂₇, R₂₈, R₂₉, R₃₀, R₃₁ is each independently selected from H, C₁₋₈hydrocarbyl group, cyclic hydrocarbyl group and heterocyclic hydrocarbylgroup with or without substituent(s); wherein X6 is missing or selectedfrom O, S, NR₃₂; wherein R₃₂ is H, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), or heterocyclic hydrocarbyl group with or withoutsubstituent(s);

R₄ is selected from H, cyano, carboxyl, C₁₋₈ hydrocarbyl group with orwithout substituent(s), and hydrocarbyloxycarbonyl group with or withoutsubstituent(s);

a is an integer between 0 and 5 (such as 1, 2, 3, 4, 5);

b is an integer between 0 and 3 (such as 1, 2, 3);

c is an integer between 0 and 30 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

d is an integer between 0 and 9 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

e is an integer between 0 and 3 (such as 1, 2, 3);

f is an integer between 0 and 3 (such as 1, 2, 3).

In another preferred example, A is missing; W is —X2C(═O)X3, wherein X2is NR₁₈ and X3 is missing, or X3 is NR₁₈ and X2 is missing; Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 1 and 6; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ iseach independently selected from H, hydroxy, C₁₋₄ hydrocarbyl group withor without substituent(s), i is an integer between 1 and 6; c is 0.

In another preferred example, A is missing; W is missing or O; Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 0 and 3; B is O; Z is (CR₂₄R₂₅)_(i), wherein R₂₄,R₂₅ is each independently selected from H, hydroxy, C₁₋₄ hydrocarbylgroup with or without substituent(s), i is an integer between 1 and 3; cis an integer between 1 and 6.

In another preferred example, A is SO₂X1; wherein XI is missing orselected from O and S; W is missing or O; Y is (CR₂₂R₂₃)_(h), whereinR₂₂ and R₂₃ is each independently selected from H, hydroxyl, and C₁₋₄hydrocarbyl group with or without substituent(s), h is an integerbetween 1 and 6; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ is eachindependently selected from H, hydroxy, and C₁₋₄ hydrocarbyl group withor without substituent(s), i is an integer between 0 and 3; c is 0.

In another preferred example, A is missing; W is NR₁₇; wherein R₁₇ is H,or C₁₋₄ hydrocarbyl group with or without substituent(s); Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 0 and 3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ iseach independently selected from H, hydroxy, and C₁₋₄ hydrocarbyl groupwith or without substituent(s), i is an integer between 1 and 4; B is O;c is an integer between 1 and 6.

In another preferred example, A is missing; W is missing; Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 0 and 3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ iseach independently selected from H, hydroxy, and C₁₋₄ hydrocarbyl groupwith or without substituent(s), i is an integer between 0 and 3; B is O;c is an integer between 1 and 10 (preferably between 1 and 6).

In another preferred example, A is C(═O)X1-, wherein XI is missing orselected from a 3- to 8-membered heteroaromatic ring (preferably such asa pyridine ring or a 1,2,3-triazole ring) with or withoutsubstituent(s), and 3- to 8-membered aromatic rings (preferably abenzene ring) with or without substituent(s).

In another preferred example, A is C(═O) and Y is C(═CH₂)(CR₂₂R₂₃)_(h),wherein h is an integer between 0 and 10 (preferably an integer between0 and 5).

In another preferred example, any of the substituents is selected fromthe group consisting of halogen, unsubstituted or halogenated C1-C6alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted orhalogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl,unsubstituted or halogenated C1-C6 alkylene-hydroxyl, unsubstituted orC1-C6 alkyl substituted amine.

In another preferred example, the structure of the compound isrepresented by formula I′:

wherein, each group is defined as described above.

In another preferred example, the structure of the compound isrepresented by formula I″:

wherein, each group is defined as described above.

In another preferred example, the structure of the compound isrepresented by formula I′″:

wherein, each group is defined as described above.

In another preferred example, in formula I, I′, I″, or I′″,

represents a single bond.

In another preferred example, X is C(═O).

In another preferred example, R₁ is selected from H and C₁₋₄ alkyl withor without substituent(s).

In another preferred example, R₂, R₅ is each independently selected fromH and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₃ is selected from H and C₁₋₄ alkyl withor without substituent(s).

In another preferred example, R₆ is selected from H, C₁₋₄ alkyl with orwithout substituent(s), and OR₂₉; wherein R₂₉ is selected from H andC₁₋₆ alkyl with or without substituent(s).

In another preferred example, R₇ is selected from H, C₁₋₄ alkyl with orwithout substituent(s), and NR₂₈R₂₉; wherein R₂₈, R₂₉ is eachindependently selected from H and C₁₋₄ hydrocarbyl group with or withoutsubstituent(s).

In another preferred example, R₈ is selected from H, halogen and C₁₋₄alkyl with or without substituent(s).

In another preferred example, R₉ is selected from H, halogen and C₁₋₄alkyl with or without substituent(s).

In another preferred example, R₁₀ is selected from H, halogen, cyano,nitro, and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₁₁ is selected from H, halogen, cyano,nitro, and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₄ is selected from H, cyano and C₁₋₆alkyl with or without substituent(s).

In the second aspect of the present invention, there is provided apharmaceutical composition, which comprises the compound according tothe first aspect or a pharmaceutically acceptable salt thereof, or aprodrug thereof, and a pharmaceutically acceptable carrier.

In another preferred example, the effective amount refers to atherapeutically effective amount or an inhibitory effective amount,preferably 0.01 to 99.99%.

In another preferred example, the pharmaceutical composition furthercomprises one or more antitumor agents.

In another preferred example, the pharmaceutical composition is used toinhibit the activity of Bruton's tyrosine kinase (Btk).

In another preferred example, the pharmaceutical composition is used fortreating diseases related to the activity or expression level ofBruton's tyrosine kinase (Btk).

In the third aspect of the present invention, there is provided a use ofthe compound according to the first aspect of the present invention for:

(a) preparation of drugs for the treatment of diseases related to theactivity or expression level of Bruton's tyrosine kinase (Btk);

(b) preparation of Bruton's tyrosine kinase (Btk) targeting inhibitorsor degradation agents;

(c) non-therapeutic inhibition or degradation of the activity ofBruton's tyrosine kinase (Btk) in vitro;

(d) non-therapeutic inhibition of tumor cell proliferation in vitro;and/or

(e) treatment of diseases related to the activity or expression level ofBruton's tyrosine kinase (Btk).

In another preferred example, the diseases include tumors and autoimmunediseases; preferably, the tumors include non-Hodgkin's lymphoma (NHL),chronic lymphocytic leukemia (CLL), B-cell lymphoma, etc.; theautoimmune diseases include rheumatoid arthritis, psoriasis, etc.

In the fourth aspect of the present invention, there is provided amethod for preparing the compound of formula I according to the firstaspect of the present invention, comprising the step of:

-   (a) reacting a compound of formula IV and a compound of formula II    in an inert solvent to obtain a compound of formula I;    -   in the above formulas, the definition of each group is as        described above, and M₁ is a leaving group.

In another preferred example, the method further comprises the step of:

-   -   W1=OH or NH₂

-   (b) reacting a compound of formula III and a compound of formula V    in an inert solvent to obtain a compound of formula II; M₁ and M₂    are leaving groups.

In the fifth aspect of the present invention, there is provided a methodfor inhibiting or degrading the activity of Bruton's tyrosine kinase(Btk), comprising the step of administering an inhibitory effectiveamount of the compound of formula I or a pharmaceutically acceptablesalt thereof according to the first aspect of the present invention toan inhibitory subject, or administering an inhibitory effective amountof the pharmaceutical composition according to the fourth aspect of thepresent invention to an inhibitory subject.

In another preferred example, the inhibition is non-therapeuticinhibition in vitro.

In another preferred example, when an inhibitory effective amount of thecompound of formula I or a pharmaceutically acceptable salt thereofaccording to the first aspect of the present invention is administeredto an inhibitory subject, the inhibitory effective amount is 0.001-500nmol/L, preferably 0.01-200 nmol/L.

In the sixth aspect of the present invention, there is provided a methodfor treating a disease related to the activity or expression level ofBruton's tyrosine kinase (Btk), comprising a step of: administering atherapeutically effective amount of the compound of formula I accordingto the first aspect of the present invention or the pharmaceuticalcomposition according to the fourth aspect of the present invention to atreating subject.

In another preferred example, the subject is a mammal; preferably, themammal is a human.

In another preferred example, the disease related to the activity orexpression level of Bruton's tyrosine kinase (Btk) is a tumor or anautoimmune disease.

In the seventh aspect of the present invention, there is provided amethod for inhibiting tumor cells in vitro, the method comprising:administering an inhibitory effective amount of the compound of formulaI according to the first aspect of the present invention or thepharmaceutical composition according to the second aspect of the presentinvention to an inhibitory subject.

It is to be understood that within the scope of the present invention,the various technical features of the present invention and the varioustechnical features specifically described hereinafter (as in theembodiments) may be combined with each other to form a new or preferredtechnical solution. Due to space limitations, we will not repeat themhere.

DETAILED DESCRIPTION OF THE INVENTION

After extensive and intensive research, the present inventors haveprepared a class of compounds having the structure shown in formula Iand have found that they have inhibitory and degradation activities onBruton's tyrosine kinase (Btk). In addition, the compound has aninhibitory effect on Bruton's tyrosine kinase (Btk) at a very lowconcentration, and the inhibitory activity is quite excellent, so it canbe used for the treatment of diseases related to the activity orexpression level of Bruton's tyrosine kinase (Btk), such as tumors. Thepresent invention has been completed on this basis.

The present invention has disclosed a new class of compounds and its usefor inhibiting and degrading Bruton's tyrosine kinase (Btk). Thesecompounds can inhibit and degrade Btk and be used to treat tumors orautoimmune diseases.

Term

In the present invention, the term “C₁₋₈ hydrocarbyl group” refers to afunctional group containing only two kinds of atoms of carbon andhydrogen, in which the number of carbon atoms is 1 to 8. A hydrocarbylgroup can be regarded as a free radical left after the correspondinghydrocarbon loses one hydrogen atom, which may be an alkyl group, acycloalkyl group, an alkenyl group, or an alkynyl group, etc.; it may belinear, branched, or cyclic; and it is aliphatic or aromatic.

The term “C₁₋₆ alkyl” refers to a straight or branched alkyl grouphaving 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

The term “alkoxy” as used herein includes O-alkyl, in which “alkyl” isas defined above.

The term “halogenated” as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo.

The compound of the present invention may contain a double bond. Whensuch double bond is contained, the compounds of the present inventionexist in cis form, trans form or mixtures thereof.

The halogens described herein include fluorine, chlorine, bromine andiodine.

Unless otherwise indicated, the alkyl and the alkyl moieties of thealkoxy group herein may be linear, branched, or cyclic.

In the present invention, the term “cyclic hydrocarbyl group” refers toa functional group containing two kind of atoms of carbon and hydrogen,and includes cycloalkyl, cycloalkenyl (containing at least onecarbon-carbon double bond), and aryl. They can be monocyclic, bicyclic,and polycyclic. They can be spiro rings or fused rings.

In the present invention, the term “heterocyclic hydrocarbyl group”refers to a functional group containing carbon, hydrogen, and at leastone heteroatom other than carbon and hydrogen. It includesheterocycloalkyl, heterocycloalkenyl (containing at least onecarbon-carbon double bond), and heteroaryl. One or more ring-formingatoms in the ring are heteroatoms. The heteroatoms can be O, N, S, orany combination thereof. They can be monocyclic, bicyclic or polycyclic.They can be spiro rings or fused rings.

In the present invention, the term “substituent” includes, but is notlimited to, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C₁₋₆hydrocarbyloxy group, C₁₋₆ halohydrocarbyl group, C₁₋₆ acyl group, C₁₋₆sulfonyl group.

The term “hydrocarbyloxy group” as used herein refers to anO-hydrocarbyl group, where the “hydrocarbyl group” is as defined above.

The term “hydrocarbyloxycarbonyl group” as used herein refers to aC(═O)O-hydrocarbyl group, in which the “hydrocarbyl group” is as definedabove.

The term “amino” as used herein refers to N(H or hydrocarbyl 1) (H orhydrocarbyl 2), in which the “hydrocarbyl group” is as defined above.

The term “aminocarbonyl group” as used herein refers to a C(═O)-aminogroup, in which the “amino” is as defined above.

The term “amido” as used herein refers to N(H or hydrocarbylgroup)-C(═O)-hydrocarbyl group, in which the “hydrocarbyl group” is asdefined above.

In the present invention, the term “containing”, “comprising” or“including” means that various ingredients can be used together in themixture or composition of the present invention. Thus, the terms“consisting essentially of” and “consisting of” are included in the term“containing”.

In the present invention, the term “pharmaceutically acceptable”ingredient refers to a substance suitable for human and/or animalswithout excessive adverse side effects (such as toxicity, irritation andallergy), that is, with a reasonable benefit/risk ratio.

In the present invention, the term “effective amount” refers to anamount of a therapeutic agent to treat, alleviate or prevent a targetdisease or condition, or an amount that exhibits a detectabletherapeutic or preventive effect. The exact effective amount for asubject will depend on the subject's size and health, the nature andextent of the condition, and the therapeutic agent and/or combination oftherapeutic agents chosen for administration. Therefore, it is notuseful to specify an accurate effective amount in advance. However, fora given condition, routine experimentation can be used to determine theeffective amount, which the clinician can determine.

As used herein, unless specifically stated, the term “substituted”refers to the replacement of one or more hydrogen atoms on a group witha substituent selected from the group consisting of: halogen,unsubstituted or halogenated C₁₋₆ alkyl, unsubstituted or halogenatedC₂₋₆ acyl, unsubstituted or halogenated C₁₋₆ alkyl-hydroxy.

Unless otherwise specified, all compounds present in the presentinvention are intended to include all possible optical isomers, such asa single chiral compound, or a mixture of various chiral compounds (ie,a racemate). Among all the compounds of the present invention, eachchiral carbon atom may optionally be in the R configuration or the Sconfiguration, or a mixture of the R configuration and the Sconfiguration.

As used herein, the term “the compound of the present invention” refersto a compound of formula I. The term also includes various crystallineforms, pharmaceutically acceptable salts, hydrates or solvates of thecompound of formula I.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt of the compound of the present invention with an acid or basesuitable for use as a medicament. The pharmaceutically acceptable saltsinclude inorganic and organic salts. One preferred class of salts issalts of the compound of the present invention with an acid. Suitableacids for forming salts include, but are not limited to, inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuricacid, nitric acid, phosphoric acid, etc., organic acids such as formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, picric acid, methanesulfonic acid, benzylsulfonic acid,benzenesulfonic acid etc.; and acidic amino acids such as aspartic acid,glutamic acid etc.

Compounds and Pharmaceutically Acceptable Salts Thereof

The present invention relates to a compound of formula I shown as belowor a pharmaceutically acceptable salt thereof;

wherein,

— refers to a single bond;

refers to a single or double bond;

A is missing or selected from C(═O), C(═O)X1-, SOX1-, SO₂X1-, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), and C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s); wherein XI is missingor selected from (CR₁₂R₁₃)_(j)O, (CR₁₂R₁₃)_(j), 3- to 8-memberedheteroaromatic ring (preferably, such as pyridyl, or 1,2,3-triazolyl)with or without substituent(s), 3- to 8-membered aromatic ring(preferably, such as phenyl) with or without substituent(s), and NR₁₄;wherein R₁₄ is H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), or C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

W is missing or selected from O, NR₁₇, —X2C(═O)X3, —X2S(═O)_(g)X3;wherein R₁₇ is independently H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s); wherein X2, X3 is each independently missing or selectedfrom O, S, and NR₁₈; wherein g is an integer between 0 and 2; whereinR₁₈ is independently H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Y is (CR₂₂R₂₃)_(h), CHX4(CR₂₂R₂₃)_(h), CX4═CH(CR₂₂R₂₃)_(h), or(CR₂₂R₂₃)_(h); wherein h is an integer between 0 and 30; wherein R₂₂,R₂₃ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X4 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), and C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Z is (CR₂₄R₂₅)_(i), CHX5(CR₂₄R₂₅)_(i), CX5═CH(CR₂₄R₂₅)_(i) orC≡C(CR₂₄R₂₅)_(i); wherein i is an integer between 0 and 30; wherein R₂₄,R₂₅ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X5 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s); B is missing or selected from O, C═O, S, NR₁₅,—NR₁₅C(═O)—, —C(═O)NR₁₅—, —C(═O)O—, OC(═O)O—, —NR₁₅C(═O)O—,—OC(═O)NR₁₅—, —NR₁₅C(═O)NR₁₆—, C₁₋₁₂ hydrocarbyl group with or withoutsubstituent(s), C₁₋₁₂ cyclic hydrocarbyl group with or withoutsubstituent(s), and C₁₋₁₂ heterocyclic hydrocarbyl group with or withoutsubstituent(s); wherein R₁₅, R₁₆ is each independently selected from H,C₁₋₈ hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), and C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

X is selected from CR₁₉R₂₀, C(═O), S(═O), SO₂, NR₂₁; wherein R₁₉, R₂₀ iseach independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein R₂₁ isselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

R₁ is selected from H, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), cyclic hydrocarbyl group with or without substituent(s),heterocyclic hydrocarbyl group with or without substituent(s) and C₁₋₆acyl group with or without substituent(s);

R₂, R₅ is each independently selected from H, OR₃₃, NR₃₄R₃₅, cyano,halogen, C₁₋₈ hydrocarbyl group with or without substituent(s), cyclichydrocarbyl group with or without substituent(s), heterocyclichydrocarbyl group with or without substituent(s), C₁₋₆ acyl group withor without substituent(s) and amido group with or withoutsubstituent(s); wherein R₃₃, R₃₄, R₃₅ is each independently selectedfrom H, C₁₋₈ hydrocarbyl group with or without substituent(s), cyclichydrocarbyl group with or without substituent(s), and heterocyclichydrocarbyl group with or without substituent(s);

R₃, R₆, R₇, R₈, R₉, R₁₀, R₁₁ is each independently selected from H,OR₂₇, NR₂₈R₂₉, cyano, halogen, nitro, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), heterocyclic hydrocarbyl group with or withoutsubstituent(s), X6S(═O)_(k)R₃₀, X6C(═O)R₃₁; wherein k is 0 to 2; whereinR₂₇, R₂₈, R₂₉, R₃₀, R₃₁ is each independently selected from H, C₁₋₈hydrocarbyl group, cyclic hydrocarbyl group and heterocyclic hydrocarbylgroup with or without substituent(s); wherein X6 is missing or selectedfrom O, S, NR₃₂; wherein R₃₂ is H, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), and heterocyclic hydrocarbyl group with or withoutsubstituent(s);

R₄ is selected from H, cyano, carboxyl, C₁₋₈ hydrocarbyl group with orwithout substituent(s), and hydrocarbyloxycarbonyl group with or withoutsubstituent(s);

a is an integer between 0 and 5 (such as 1, 2, 3, 4, 5);

b is an integer between 0 and 3 (such as 1, 2, 3);

c is an integer between 0 and 30 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

d is an integer between 0 and 9 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

e is an integer between 0 and 3 (such as 1, 2, 3);

f is an integer between 0 and 3 (such as 1, 2, 3).

Unless otherwise specified, the integer described herein is 0, 1, 2, 3,4, 5, 6, 7, 8, or 9. In another preferred example, each of the C₁₋₈cyclic hydrocarbyl groups is preferably a C₃₋₈ cyclic hydrocarbyl group(such as a C₃₋₈ cycloalkyl).

In another preferred example, each C₁₋₈ heterocyclic hydrocarbyl groupis preferably a C₃₋₈ heterocyclic hydrocarbyl group (such as a 4- to10-membered heterocycloalkyl group having 3-8 carbon atoms).

In a preferred embodiment of the present invention, the compound isselected from the following group consisting of:

Compound No. Structure  3

 7

10

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

39

40

41

43

44

The compound of the present invention may form a pharmaceuticallyacceptable salt with an inorganic acid, an organic acid or a base. Theinorganic acid includes, but is not limited to, hydrochloric acid,hydrobromic acid, nitric acid, perchloric acid, sulfuric acid, orphosphoric acid; the organic acid includes, but is not limited to,methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalicacid, acetic acid, maleic acid, ascorbic acid, lactic acid, tartaricacid, malonic acid, glycolic acid, succinic acid, and propionic acid;the bases include, but are not limited to, inorganic salts and amines.

The term of a pharmaceutically acceptable salt refers to those saltswhich, according to medical judgment, are suitable for use in contactwith human and mammalian tissues without excessive toxicity, irritation,allergic reactions, and the like. Pharmaceutically acceptable salts arewell known in the art.

The present invention also encompasses pharmaceutical compositionscontaining a prodrug of a compound of formula I. Prodrugs include thosecompounds in which the precursor molecule is covalently bonded to thefree carboxyl, hydroxyl, amino group of the compound of formula I via acarbonate bond, a urethane bond, an amide bond, an alkyl ester bond, aphosphate bond, or a phosphoramidate bond.

Preparation of Compounds

Preparation Method

The method for preparing the compound of formula I according to thepresent invention is described in more detail below, but these specificmethods do not constitute any limitation to the present invention. Thecompound of the present invention can also be conveniently prepared bycombining various synthetic methods described in the specification orknown in the art, and such combination can be easily performed by thoseskilled in the art to which the present invention belongs.

The following reaction schemes illustrate the preparation of compoundsof the present invention. Unless otherwise indicated, A, B, W, Y, Z, X,M₁, M₂, a, b, c, d, e, f, g, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁ in the reaction scheme and subsequent discussions are as definedabove.

In general, compounds of formula I can be obtained from those of formulaIII as described in the following schemes:

Compound II, in which W is an ether, can be prepared by directlynucleophilic substitution of formula III (W1=OH) with an intermediatecontaining a leaving group under the action of a base, or by aphoto-extension reaction with an alcohol; in which W is an ester orcarbamate (NHCO₂), it can be prepared by reacting formula III (W1=OH)with an acyl chloride, an activated ester (amide), a carboxylic acid, oran isocyanate under the action of a base; in which W is an amine, it canbe prepared by directly nucleophilic substitution of formula III(W1=NH₂) with an intermediate containing a leaving group under theaction of a base, or by reductive amination reaction of formula III(W1=NH₂) with an aldehyde/ketone; in which W it is an amide,alkoxycarbonylamine (OCONH) or urea, it can be prepared by reactingformula III (W1=NH₂) with the corresponding acyl chloride, activatedester (amide), carboxylic acid and isocyanate under the action of abase.

Compound I, in which A and a nitrogen atom are connected by a C—N bond,can be prepared by direct substitution reaction or reductive aminationreaction; in which A and a nitrogen atom are connected by an amide,urea, carbamate, sulfonamide, or sulfamide form, it can be prepared byusing the corresponding acyl chloride, activated ester (amide),carboxylic acid, isocyanate, sulfonyl chloride, or sulfuryl chloride.

Generally, according to the connection structure of A and W, compound Ican also be obtained by first connecting formula IV with theintermediate chain and then reacting with formula III. The chemicalsynthesis method used is the same as described above.

Compounds of formula III or IV can be obtained by known syntheticmethods or can be easily obtained commercially.

Use of Compounds of Formula I

The compound of formula I can be used for one or more of the followingpurposes:

(a) preparation of medicament for the treatment of diseases related tothe activity or expression level of Bruton's tyrosine protein kinase(Btk);

-   -   (b) preparation of Bruton's tyrosine protein kinase (Btk)        targeting inhibitors or degradation agents;    -   (c) non-therapeutic inhibition or degradation of the activity of        Bruton's tyrosine protein kinase (Btk) in vitro;    -   (d) non-therapeutic inhibition of tumor cell proliferation in        vitro; and/or    -   (e) treatment of diseases related to the activity or expression        level of Bruton's tyrosine protein kinase (Btk).

In another preferred example, the disease related to the activity orexpression level of Bruton's tyrosine protein kinase (Btk) is a tumor,preferably a tumor selected from the group consisting of non-small celllung cancer, inflammatory myofibroblastic tumor and so on.

The compound of formula I of the present invention can be used toprepare a pharmaceutical composition, which comprises: (i) an effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof; and (ii) a pharmaceutically acceptable carrier.

In another preferred example, the effective amount refers to atherapeutically effective amount or an inhibitory effective amount.

The compound of formula I of the present invention can also be used in amethod for inhibiting or degrading Bruton's tyrosine protein kinase(Btk), and the inhibition is a non-therapeutic inhibition in vitro or atherapeutic inhibition.

In another preferred example, when an inhibitory effective amount of thecompound of formula I of the present invention or a pharmaceuticallyacceptable salt thereof is administered to an inhibitory subject, theinhibitory effective amount is 0.001-500 nmol/L, preferably 0.01-200nmol/L.

In particular, the present invention also provides a method of treatinga disease related to the activity or expression level of Bruton'styrosine protein kinase (Btk), and the method comprising: administeringa therapeutically effective amount of a compound of formula I or apharmaceutical composition containing the compound of formula I as anactive ingredient to a subject.

Pharmaceutical Composition and Administration

Since the compound of the present invention has excellent inhibitoryactivity on Bruton's tyrosine kinase (Btk), the compound of the presentinvention and its various crystal forms, pharmaceutically acceptableinorganic or organic salts, hydrates or solvates and the pharmaceuticalcomposition containing the compound of the present invention as a mainactive ingredient can be used for treating, preventing, and alleviatingdiseases related to Btk activity or expression level. According to theprior art, the compounds of the present invention are useful fortreating diseases including tumors and the like.

The pharmaceutical composition of the present invention comprises thecompound of the present invention or the pharmaceutically acceptablesalts thereof in a safe and effective dosage range and pharmaceuticallyacceptable excipients or carriers. The “safe and effective amount” meansthe amount of the compound is sufficient to significantly improve thecondition, but will not have serious side effects. Generally, thepharmaceutical composition contains 1-2000 mg of the compound of thepresent invention per dose, preferably, 2-500 mg the compound of thepresent invention per dose. Preferably, “one dose” is a capsule ortablet.

“Pharmaceutically acceptable carrier” means one or more compatible solidor liquid fillers or gelatinous materials which are suitable for humanuse and should be of sufficient purity and sufficiently low toxicity.“Compatible” herein means that each component in the composition and acompound of the present invention can be well blended with each otherbetween them, without significantly reducing the efficacy of thecompounds. Some examples of pharmaceutically acceptable carriers includecellulose and the derivatives thereof (such as sodium carboxymethylcellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin,talc, solid lubricants (such as stearic acid, magnesium stearate),calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanutoil, olive oil, etc.), polyols (such as propylene glycol, glycerol,mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agent(such as sodium dodecyl sulfate), coloring agents, flavoring agents,stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There is no special limitation of administration mode for the compoundor pharmaceutical compositions of the present invention, and therepresentative administration mode includes (but is not limited to):oral, intratumoral, rectal, parenteral (intravenous, intramuscular orsubcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In these solid dosage forms, the activecompounds are mixed with at least one conventional inert excipient (orcarrier), such as sodium citrate or dicalcium phosphate, or mixed withany of the following components: (a) fillers or compatibilizer, forexample, starch, lactose, sucrose, glucose, mannitol and silicic acid;(b) binders, for example, hydroxymethyl cellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as,glycerol; (d) disintegrating agents such as agar, calcium carbonate,potato starch or tapioca starch, alginic acid, certain compositesilicates, and sodium carbonate; (e) dissolution-retarding agents, suchas paraffin; (f) absorption accelerators, for example, quaternaryammonium compounds; (g) wetting agents, such as cetyl alcohol andglyceryl monostearate; (h) adsorbents, for example, kaolin; and (i)lubricants such as talc, stearin calcium, magnesium stearate, solidpolyethylene glycol, sodium lauryl sulfate, or the mixtures thereof. Incapsules, tablets and pills, the dosage forms may also contain bufferingagents.

The solid dosage forms such as tablets, sugar pills, capsules, pills andgranules can be prepared by using coating and shell materials, such asenteric coatings and any other materials known in the art. They cancontain an opaque agent and the release of the active compounds orcompounds in the compositions can be released in a delayed mode in agiven portion of the digestive tract. Examples of the embeddingcomponents include polymers and waxes. If necessary, the activecompounds and one or more above excipients can form microcapsules.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups or tinctures. Inaddition to the active compounds, the liquid dosage forms may containany conventional inert diluents known in the art such as water or othersolvents, solubilizers and emulsifiers, for example, ethanol,isopropanol, ethyl carbonate, ethyl acetate, propylene glycol,1,3-butanediol, dimethyl formamide, as well as oil, in particular,cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil andsesame oil, or the combination thereof.

Besides these inert diluents, the composition may also contain additivessuch as wetting agents, emulsifiers and suspending agent, sweetener,flavoring agents and perfume.

In addition to the active compounds, the suspension may containsuspending agent, for example, ethoxylated isooctadecanol,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, methanol aluminum and agar, or the combination thereof.

The compositions for parenteral injection may comprise physiologicallyacceptable sterile aqueous or anhydrous solutions, dispersions,suspensions or emulsions, and sterile powders which can be re-dissolvedinto sterile injectable solutions or dispersions. Suitable aqueous andnon-aqueous carriers, diluents, solvents or excipients include water,ethanol, polyols and any suitable mixtures thereof.

The dosage forms for topical administration of compounds of the presentinvention include ointments, powders, patches, aerosol, and inhalants.The active ingredients are mixed with physiologically acceptablecarriers and any preservatives, buffers, or propellant if necessary,under sterile conditions.

Compounds of the present invention can be administrated alone, or incombination with any other pharmaceutically acceptable compounds.

When the pharmaceutical compositions are used, a safe and effectiveamount of compound of the present invention is applied to a mammal (suchas human) in need of, in which the dose of administration is apharmaceutically effective dose. For a person weighed 60 kg, the dailydose is usually 1-2000 mg, preferably 5-500 mg. Of course, theparticular dose should also depend on various factors, such as the routeof administration, the healthy condition of patient, which are wellwithin the skills of an experienced physician.

The main advantages of the present invention include:

1. Compounds of formula I are provided.

2. A novel Btk inhibitor and preparation and application thereof areprovided. The inhibitor can inhibit the activity of Btk at very lowconcentrations.

3. A pharmaceutical composition for treating diseases related to Btkactivity is provided.

The present invention will be further illustrated below with referenceto the specific examples. It should be understood that these examplesare only to illustrate the invention but not to limit the disclosure ofthe invention. The experimental methods without specific conditions inthe following embodiments are generally carried out according toconventional conditions, or in accordance with the conditionsrecommended by the manufacturer. Unless stated otherwise, percentagesand parts are percentages by weight and parts by weight.

Example 1 Preparation of Compound 3

Step 1:

2.14 g of 6-bromohexanoyl chloride and 1.37 g of pomalidomide weredissolved in 50 ml of tetrahydrofuran. The mixture was stirred at refluxfor 8 h, then cooled to room temperature and concentrated under vacuumat 40° C. to obtain 1.22 g of compound (1). MS (ESI): 450 [M+H]⁺.

Step 2:

860 mg of compound (1), 1 g of compound (2) and 0.60 g ofdiisopropylethylamine were dissolved in 30 ml of DMF (N,N-dimethylformamide). The mixture was stirred at 80° C. for 6 h, andthen cooled to room temperature. After concentration, the residue waspurified by column chromatography to obtain 408 mg of compound (3) witha yield of 31.2%. MS (ESI): 756 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ10.32-10.14 (m, 1H), 9.43 (s, 1H), 8.83 (d, J=8 Hz, 1H), 8.42 (d, J=8Hz, 1H), 1 FI (t, 1H), 8.83 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 1H), 7.39(t, 3H), 7.17 (m, 3H), 7.08 (d, J=8 Hz, 2H), 5.81 (s, 2H), 5.02-4.95 (m,2H), 3.17 (d, J=8 Hz, 1H), 2.86-2.76 (m, 2H), 2.66-2.55 (m, 1H),2.49-2.46 (m, 3H), 2.19-2.06 (m, 3H), 1-86 (m, 2H), 1.80-1.76 (m, 2H),1.59-1.56 (m, 2H), 1.44-1.42 (m, 2H), 1.29-1.26 (m, 1H), 0.8-0.7 (m,1H).

Example 2 Preparation of Compound 7

Step 1:

100 mg of 4-hydroxythalidomide, 96 mg of triethylene glycol monobenzylether, and 100 mg of triphenylphosphine were dissolved in 10 ml ofanhydrous THF, and then 95 mg of DIAD (diisopropyl azodicarboxylate) wasadded dropwise. The reaction was carried out at room temperature for 2h. THF was removed under reduced pressure, and 110 mg of compound (4)was obtained after purification by column chromatography. MS (ESI): 497[M+H]⁺.

Step 2:

100 mg of compound (4) and 100 mg of 10% Pd—C were added into 10 ml ofmethanol and the mixture was hydrogenated at room temperature overnight.Then the mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography to obtain 40 mg ofcompound (5). MS (ESI): 407 [M+H]⁺.

Step 3:

30 mg of compound (5) was dissolved in 5 ml of dichloromethane, and then47 mg of Dess-martin oxidant was added. The mixture was reacted at roomtemperature for 3 h. A saturated aqueous solution of NaHCO₃ and asaturated aqueous solution of Na₂S₂O₃ were added to the reaction system,and stirred for 5 min. The organic layer was separated, dry overanhydrous Na₂S₂O₃, and concentrate to dryness. The obtained compound (6)is directly used in the next step.

After compound (6) was dissolved in 7 ml of dichloromethane, 50 mg ofraw material (2) and 30 mg of NaBH(OAc)₃ were added, and the mixture wasreacted overnight at room temperature. Dichloromethane was distilled offunder reduced pressure. 35 mg of compound (7) was obtained afterpurification by column chromatography. MS (ESI): 775 [M+H]⁺. ¹H NMR (400MHz, CDCl3) δ 9.63-9.96 (br, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.60-7.66 (m,3H), 7.44 (d, J=7.2 Hz, 1H), 7.38 (m, 2H), 7.22 (dd, J=8.4, 1.6 Hz, 1H),7.11-7.19 (m, 3H), 7.07 (d, J=8.4 Hz, 2H), 5.75 (br, 2H), 4.91-5.05 (m,2H), 4.29 (t, J=4.8 Hz, 2H), 3.91 (m, 2H), 3.75 (m, 2H), 3.62 (m, 4H),3.21 (br, 1H), 2.97 (br, 1H), 2.60-2.91 (m, 6H), 2.05-2.20 (m, 4H), 1.83(m, 2H).

Example 3 Preparation of Compound 10

Step 1:

174 mg of benzyl 2-(2-(2-bromoethoxy)ethoxy)acetate, 100 mg of potassiumcarbonate, 20 mg of potassium iodide and 100 mg of pomalidomide wereadded into 20 ml of DMF (N, N-dimethylformamide), and reacted at 80° C.overnight. The reaction solution was purified by column chromatographyto obtain 113 mg of compound (8). MS (ESI): 510 [M+H]⁺.

Step 2:

100 mg of compound (8) and 100 mg of 10% Pd—C were added into 10 ml ofmethanol and the mixture was hydrogenated at room temperature overnight.Then the mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography to obtain 73 mg ofcompound (9). MS (ESI anion): 418 [M−H]⁻.

Step 3:

50 mg of compound (9) and 50 mg of raw material (2) were dissolved in 5ml of dichloromethane, and 20 mg of HOBt (1-hydroxybenzotriazole) and 40mg of EDC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride)were added. The mixture was reacted at room temperature overnight.Dichloromethane was distilled off under reduced pressure, and 41 mg ofcompound (10) was obtained after purification by column chromatography.MS (ESI): 788 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 9.90-10.22 (br, 1H),8.37 (d, J=7.6 Hz, 1H), 7.62 (m, 2H), 7.45 (m, 1H), 7.38 (t, J=7.6 Hz,2H), 7.04-7.18 (m, 6H), 6.87 (d, J=8.8 Hz, 1H), 6.47 (m, 1H), 5.81 (br,2H), 5.01 (m, 1H), 4.90 (m, 1H), 4.65 (s, 2H), 3.63-3.72 (m, 6H), 3.25(br, 1H), 2.62-3.04 (m, 7H), 2.06-2.20 (m, 4H), 1.83 (m, 2H).

Example 4 Preparation of Compound 13

Step 1:

200 mg of the raw material (2) was dissolved in 20 ml ofdichloromethane, 100 mg of triethylamine and 150 mg of5-benzyloxypentanesulfonyl chloride were added, and the mixture wasreacted at room temperature overnight. The solvent was removed underreduced pressure, and 233 mg of compound (11) was obtained afterpurification by column chromatography. MS (ESI): 627 [M+H]⁺.

Step 2:

200 mg of compound (11) and 200 mg of 10% Pd—C were added into 20 ml ofmethanol and the mixture was hydrogenated at room temperature overnight.Then the mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography to obtain 155 mg ofcompound (12). MS (ESI): 536[M+H]⁺.

Step 3:

50 mg of 4-hydroxythalidomide, 50 mg of triphenylphosphine and 80 mg ofcompound (12) were dissolved in 5 ml of anhydrous tetrahydrofuran, 50 mgof DIAD (diisopropyl azodicarboxylate) was added dropwise, and thereaction was carried out at room temperature for 3 h. Tetrahydrofuranwas removed under reduced pressure, and 41 mg of compound (13) wasobtained after purification by column chromatography. MS (ESI): 793[M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 9.83-9.95 (br, 1H), 8.38 (d, J=7.6 Hz,1H), 7.60-7.75 (m, 3H), 7.45 (m, 1H), 7.39 (t, J=7.2 Hz, 2H), 7.00-7.19(m, 5H), 6.85 (d, J=8.4 Hz, 1H), 5.81 (br, 2H), 5.03 (m, 1H), 4.92 (m,1H), 3.95 (t, J=7.2 Hz, 2H), 3.45 (m, 2H), 3.26 (br, 1H), 2.60-3.02 (m,7H), 2.06-2.20 (m, 4H), 1.70-1.95 (m, 4H), 1.35 (br, 2H).

Similarly, the following compounds were prepared by a method similar tothe above example:

Reference Com- example for pound synthesis MS No. Structure of compoundmethod (ESI) 14

2, 3 774 [M + H]⁺ 15

2, 3 818 [M + H]⁺ 16

2 819 [M + H]⁺ 17

2, 3 829 [M + H]⁺ 18

2, 3 873 [M + H]⁺ 19

2, 3 887 [M + H]⁺ 20

2, 3 901 [M + H]⁺ 21

2, 3 903 [M + H]⁺ 22

2, 3 917 [M + H]⁺ 23

3 828 [M + H]⁺ 24

3 872 [M + H]⁺ 25

3 886 [M + H]⁺ 26

3 900 [M + H]⁺ 27

3 902 [M + H]⁺ 28

3 916 [M + H]⁺ 29

2, 3 843 [M + H]⁺ 30

2, 3 829 [M + H]⁺ 31

2, 3 873 [M + H]⁺ 32

2, 3 917 [M + H]⁺ 33

3 842 [M + H]⁺ 34

3 828 [M + H]⁺ 35

3 872 [M + H]⁺ 36

3 916 [M + H]⁺ 37

2, 3 870 [M + H]⁺ 39

2, 3 914 [M + H]⁺ 40

2, 3 958 [M + H]⁺ 41

3 869 [M + H]⁺ 43

3 913 [M + H]⁺ 44

3 957 [M + H]⁺

Example 5 Testing the Inhibition Activity of Compounds on Btk by CaliperAssay

The experimental steps were as follows:

Preparation of 1× kinase reaction buffer (50 mM HEPES, PH 7.5; 0.0015%Brij-35) and kinase reaction termination solution (100 mM HEPES, PH 7.5;0.0015% Brij-35; 0.2% Coating Reagent; 50 mM EDTA);

Preparation of experimental samples: 100 μL of 5 μM sample solution(dissolved in 100% DMSO) was added to a 96-well plate to obtain a 50×sample solution. As a control, two wells were set containing only 100 μLof 100% DMSO on the same plate. One was served as a control withoutsamples and the other was served as a control without enzymes. 10 μL ofsample and 90 μL of 1× kinase reaction buffer were added to a 96-wellplate as a transfer plate. The transfer plate was shaken for 10 minutes.

Preparation of the test plate: taking 5 μL each of the prepared samplesin the 96-well transfer plate into a 384-well plate.

Kinase reaction: to 5 μL of 5× compound solution (dissolved in DMSO,diluted 10 times with water) was added 10 μL of 2.5×Btk kinase solution(kinase was diluted with 1× kinase reaction buffer), and incubated atroom temperature for 10 min, then 10 μL of 2.5× substrate peptidesolution (FAM-labeled peptide and ATP were diluted with 1× kinasereaction buffer) was added.

Termination of the kinase reaction: 25 μL of kinase termination solutionwas added after being reacted at 28° C. for a period of time.

The fluorescence (F) was tested on a Caliper and data was collected.

The inhibition rate of kinase activity was calculated: the percentinhibition rate of kinaseactivity=(F_(DMSO control)−F_(sample))/(F_(DMSO control)−F_(negative control))×100,with DMSO as the solution control, and no kinase as the negativecontrol.

The results show that the inhibitory activity of compound (100 nM) onBtk is shown in the following table:

Compound No. Inhibition(%) 3 92 7 99 14 99 15 98 16 95

Example 6 Testing the Btk Protein Degradation Activity of Compounds byWestern Blot

Cell lines: RPMI8226 Cell line was cultured in RPMI1640 mediumcontaining 10% calf serum in a 37° C., 5% CO₂, and saturated humidityincubator.

DMSO control group and compound intervention group (10 μM) were set.Cells was collected after the treatment for 24 horns, then 100 μL ofpre-chilled cell lysate was added and cells were lysed on ice for 30minutes. Total cell protein was extracted, and protein concentration wasdetermined and quantified by diquinolinecarboxylic acid (BCA) method.After routine gelatinization, loading, electrophoresis, thentransferring to membrane and blocking, rabbit anti-human Btk (1:500) wasadded, and incubated at 4° C. overnight. The mixture was rinsed and thenhorseradish peroxidase labeled goat anti-rabbit IgG (1:5000) was added.After the rinsing it was developed by the ECL developing solution, theBio-Rad gel imaging system was used for scanning and imaging, and thecomputer software was used for analysis. Glycerol phosphatedehydrogenase (GAPDH) was used as an internal control.

Image J software was used to analyze the gray scale of each band tocalculate the Btk protein 15 degradation rate of the compound.

The results show that the degradation activity of the compound (10 μM)on Btk protein in RPMI8226 cells is shown in the following table:

Compound Degradation No. activity 3 ++++ 7 ++++ 14 ++++ 15 ++++ 16 ++++17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 ++++ 24 ++++ 25 ++++ 26++++ 27 ++++ 28 +++ 29 ++++ 30 ++++ 31 ++++ 32 +++ 33 ++++ 34 ++++ 35++++ 36 +++ 37 ++++ 39 ++++ 40 +++ 41 +++ 43 ++++ 44 +++ control −compound

Note: in the above table, represents no degradation activity, “+”represents a degradation rate of 10%-30%, “++” represents a degradationrate of 30%-50%, and “+++” represents a degradation rate of 50%-90%, and“++++” means the degradation rate is greater than 90%. The structure ofthe control compound is as follows:

Example 7 Testing the Inhibitory Effect of Formula Compounds on theProliferation of RPMI 8226 Cells (Human Multiple Myeloma Cells) by CCK8Assay

The inhibitory effect of the compound on the proliferation of RPMI 8226cells (commercially available from ATCC) was determined by the CCK8assay in vitro. The experimental steps were as follows:

RPMI 8226 cells were cultured in 1640 medium containing 10% calf serum,seeded in a 96-well plate with 2×10⁵ cells/well, and placed in a 37° C.,5% CO₂ incubator. The compound was dissolved in dimethyl sulfoxide(DMSO) to obtain a solution with a concentration of 10 mM, and thendiluted to the desired concentration with a phosphate buffer solution.The solution was added to the above 96-well plate. Each concentrationhas 2 wells with 10 μl per well. Each concentration was tested induplicate. As a control, DMSO was diluted in the corresponding gradientand then added to the plate.

After the 96-well plate was cultured in a 37° C., 5% CO₂ cell incubatorfor 48 horns, 10 μl of CCK8 solution was added to each well, and it wascultured in the incubator for another 1 to 4 hours. The light absorptionvalue at 465 nm was measured.

The relative survival rate of the cells after the compound treatment wascalculated based on the light absorption value.

The IC₅₀ of the compound against RPMI 8226 cells was calculated bysoftware.

The inhibitory effect of synthesized compounds on RPMI 8226 cells invitro is shown in the following table:

Compound No. IC₅₀ (μM) 3 34 7 83 14 6

Activity test data shows that the compounds of the present inventionhave significant inhibitory activity on Ibrutinib-resistant cell lines,so the compounds of the present invention can be used to treatIbrutinib-resistant tumors.

Example 8 Testing the Inhibitory Effect of Formula Compounds on theProliferation of DOHH2 Cells (Human B Cell Lymphoma Cells) and SU-DHL-6(Human B Cell Lymphoma Cells) by CTG Assay

The CCK8 assay was used to determine the inhibitory effect of thecompounds on the proliferation of DOHH2 cells (available from ATCC) andSU-DHL-6 cells (available from ATCC) in vitro. Cells were cultured andcompounds were prepared referring to Example 7. The cell plating densitywas 1×10⁴ cells/well for DOHH2 cells, and 1.5×10⁴ cells/well forSU-DHL-6 cells. The culture time after the administration was 72 hours.After that an appropriate amount of CTG reagent was added, theluminescence value was measured, and the inhibition rate was calculated.

The inhibitory effect of the synthesized compound (10 μM) on DOHH2 andSU-DHL-6 cells in vitro is shown in the table below.

Compound Inhibition(%) No. DOHH2 SU-DHL-6 3 87% 60% 7 63% 53% 14 98% 87%15 99% 94% 16 84% 71%

All publications mentioned herein are incorporated by reference as ifeach individual document is cited as a reference, as in the presentapplication. It should also be understood that, after reading the aboveteachings of the present invention, those skilled in the art can makevarious changes or modifications, equivalents of which fall in the scopeof claims as defined in the appended claims.

1-10. (canceled)
 11. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein: each

is independently a single or double bond; A is absent or selected fromC(═O), C(═O)X₁; SOX₁, SO₂X₁, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl,and C₁₋₈ heterocyclic hydrocarbyl; wherein X₁ is absent or selected from(CR₁₂R₁₃)_(j)O, (CR₁₂R₁₃)_(j)S, 3- to 8-membered heteroaromatic ring, 3-to 8-membered aromatic ring and NR₁₄; wherein R₁₂, R₁₃, R₁₄ is eachindependently H, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, or C₁₋₈heterocyclic hydrocarbyl; j is an integer between 0 and 3; wherein eachC₁₋₈ heterocyclic hydrocarbyl independently contains one or moreheteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur, and further wherein each C₁₋₈ hydrocarbyl,C₁₋₈ cyclic hydrocarbyl, and C₁₋₈ heterocyclic hydrocarbyl is optionallyand independently substituted; W is absent or selected from O, NR₁₇, andX₂C(═O)X₃; wherein R₁₇ is H, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl,or C₁₋₈ heterocyclic hydrocarbyl; wherein X₂, X₃ is each independentlyabsent or selected from O, S and NR₁₈; wherein R₁₈ is H, C₁₋₈hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, or C₁₋₈ heterocyclic hydrocarbyl;wherein each C₁₋₈ heterocyclic hydrocarbyl independently contains one ormore heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur; and further wherein each C₁₋₈ hydrocarbyl,C₁₋₈ cyclic hydrocarbyl, and C₁₋₈ heterocyclic hydrocarbyl is optionallyand independently substituted; Y is (CR₂₂R₂₃)_(h), CHX₄(CR₂₂R₂₃)_(h),CX₄═CH(CR₂₂R₂₃)_(h), or C(═CH₂)(CR₂₂R₂₃)_(h); wherein h is an integerbetween 0 and 30; wherein R₂₂, R₂₃ is each independently selected fromH, cyano, hydroxyl, amino, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl,C₁₋₈ heterocyclic hydrocarbyl, and C₁₋₈ hydrocarbyloxy; wherein X₄ is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy, C₁₋₈hydrocarbyloxycarbonyl, C₁₋₈ amino, C₁₋₈ ester, C₁₋₈ aminocarbonyl, C₁₋₈hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, or C₁₋₈ heterocyclic hydrocarbyl;wherein each C₁₋₈ heterocyclic hydrocarbyl independently contains one ormore heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur; and further wherein each C₁₋₈hydrocarbyloxy, C₁₋₈ hydrocarbyloxycarbonyl, C₁₋₈ amino, C₁₋₈ ester,C₁₋₈ aminocarbonyl, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, and C₁₋₈heterocyclic hydrocarbyl is optionally and independently substituted; Zis (CR₂₄R₂₅)_(i), CHX₅(CR₂₄R₂₅)_(i), CX₅═CH(CR₂₄R₂₅)_(i) orC≡C(CR₂₄R₂₅)_(i); wherein i is an integer between 0 and 30; wherein R₂₄,R₂₅ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, C₁₋₈ heterocyclic hydrocarbyl, andC₁₋₈ hydrocarbyloxy; wherein X₅ is H, halogen, cyano, nitro, hydroxyl,C₁₋₈ hydrocarbyloxy, C₁₋₈ hydrocarbyloxycarbonyl, C₁₋₈ amino, C₁₋₈ester, C₁₋₈ aminocarbonyl, C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, orC₁₋₈ heterocyclic hydrocarbyl; wherein each C₁₋₈ heterocyclichydrocarbyl independently contains one or more heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur; andfurther wherein each C₁₋₈ hydrocarbyloxy, C₁₋₈ hydrocarbyloxycarbonyl,C₁₋₈ amino, C₁₋₈ ester, C₁₋₈ aminocarbonyl, C₁₋₈ hydrocarbyl, C₁₋₈cyclic hydrocarbyl, and C₁₋₈ heterocyclic hydrocarbyl is optionally andindependently substituted; B is absent or selected from O, C═O, S, NR₁₅,NR₁₅C(═O), C(═O)NR₁₅, C(═O)O, OC(═O)O, NR₁₅C(═O)O, OC(═O)NR₁₅,NR₁₅C(═O)NR₁₆; wherein R₁₅, R₁₆ is each independently selected from H,C₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, and C₁₋₈ heterocyclichydrocarbyl; wherein each C₁₋₈ heterocyclic hydrocarbyl independentlycontains one or more heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur; and further wherein eachC₁₋₈ hydrocarbyl, C₁₋₈ cyclic hydrocarbyl, and C₁₋₈ heterocyclichydrocarbyl is optionally and independently substituted; X is selectedfrom CR₁₉R₂₀, C(═O), S(═O), SO₂, NR₂₁; wherein R₁₉, R₂₀ is eachindependently selected from H, cyano, hydroxyl, amino, C₁₋₈ hydrocarbyl,C₁₋₈ cyclic hydrocarbyl, C₁₋₈ heterocyclic hydrocarbyl, and C₁₋₈hydrocarbyloxy; wherein R₂₁ is selected from H, C₁₋₈ hydrocarbyl, C₁₋₈cyclic hydrocarbyl, and C₁₋₈ heterocyclic hydrocarbyl; wherein each C₁₋₈heterocyclic hydrocarbyl independently contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur; and further wherein each C₁₋₈ hydrocarbyl, C₁₋₈ cyclichydrocarbyl, and C₁₋₈ heterocyclic hydrocarbyl is optionally andindependently substituted; R₁ is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C(O)H, C(O)C₁₋₆ hydrocarbyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, heterocyclic hydrocarbyl, or phenyl, wherein theheterocyclic hydrocarbyl contains one or more heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur, andfurther wherein the C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C(O)C₁₋₆hydrocarbyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, heterocyclichydrocarbyl, or phenyl is optionally substituted; each R₂ isindependently H, F, Cl, Br, I, CN, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C(O)H, C(O)C₁₋₆ hydrocarbyl, C(O)NH₂, C(O)NHC₁₋₆ hydrocarbyl,C(O)N(C₁₋₆ hydrocarbyl)₂, NR₃₄R₃₅, OR₃₃, cyclic hydrocarbyl, orheterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl containsone or more heteroatoms independently selected from the group consistingof nitrogen, oxygen, and sulfur, and further wherein each C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C(O)C₁₋₆ hydrocarbyl, C(O)NHC₁₋₆hydrocarbyl, C(O)N(C₁₋₆ hydrocarbyl)₂, cyclic hydrocarbyl, andheterocyclic hydrocarbyl is optionally and independently substituted;each R₃ is independently H, F, Cl, Br, I, CN, NO₂, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, NR₂₈R₂₉, OR₂₇, X₆C(O)R₃₁, X₆S(O)_(k)R₃₀, cyclichydrocarbyl, or heterocyclic hydrocarbyl; wherein k is 0, 1, or 2; eachX₆ is independently absent, NR₃₂, or S; wherein each heterocyclichydrocarbyl independently contains one or more heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur, andfurther wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclichydrocarbyl, and heterocyclic hydrocarbyl is optionally andindependently substituted; each R₄ is independently H, CN, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C(O)OH, or C(O)O(hydrocarbyl), wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C(O)O(hydrocarbyl) isoptionally and independently substituted; each R₅ is independently H, F,Cl, Br, I, CN, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C(O)H, C(O)C₁₋₆hydrocarbyl, C(O)NH₂, C(O)NHC₁₋₆ hydrocarbyl, C(O)N(C₁₋₆ hydrocarbyl)₂,NR₃₄R₃₅, OR₃₃, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, whereinthe heterocyclic hydrocarbyl contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C(O)C₁₋₆ hydrocarbyl, C(O)NHC₁₋₆ hydrocarbyl, C(O)N(C₁₋₆hydrocarbyl)₂, cyclic hydrocarbyl, and heterocyclic hydrocarbyl isoptionally and independently substituted; R₆ is independently H, F, Cl,Br, I, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, NR₂₈R₂₉, OR₂₇,X₆C(O)R₃₁, X₆S(O)_(k)R₃₀, cyclic hydrocarbyl, or heterocyclichydrocarbyl; each X₆ is independently absent, NR₃₂, or S; wherein eachheterocyclic hydrocarbyl independently contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionallyand independently substituted; R₇ is independently H, F, Cl, Br, I, CN,NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, NR₂₈R₂₉, OR₂₇, X₆C(O)R₃₁,X₆S(O)_(k)R₃₀, cyclic hydrocarbyl, or heterocyclic hydrocarbyl; each X₆is independently absent, NR₃₂, or S; wherein each heterocyclichydrocarbyl independently contains one or more heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur, andfurther wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclichydrocarbyl, and heterocyclic hydrocarbyl is optionally andindependently substituted; each R₈ is independently H; each R₉ isindependently H; R₁₀ is H; each R₁₁ is independently H; each R₃₃ isindependently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclichydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclichydrocarbyl contains one or more heteroatoms independently selected fromthe group consisting of nitrogen, oxygen, and sulfur, and furtherwherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl,and heterocyclic hydrocarbyl is optionally and independentlysubstituted; each R₃₄ is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein theheterocyclic hydrocarbyl contains one or more heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur, andfurther wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclichydrocarbyl, and heterocyclic hydrocarbyl is optionally andindependently substituted; each R₃₅ is independently H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl,wherein the heterocyclic hydrocarbyl contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionallyand independently substituted; each R₂₇ is independently H, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, or heterocyclichydrocarbyl, wherein each heterocyclic hydrocarbyl independentlycontains one or more heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur, and further wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, andheterocyclic hydrocarbyl is optionally and independently substituted;each R₂₈ is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein eachheterocyclic hydrocarbyl independently contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionallyand independently substituted; each R₂₉ is independently H, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, or heterocyclichydrocarbyl, wherein each heterocyclic hydrocarbyl independentlycontains one or more heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur, and further wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, andheterocyclic hydrocarbyl is optionally and independently substituted;each R₃O is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein eachheterocyclic hydrocarbyl independently contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionallyand independently substituted; each R₃₁ is independently H, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, or heterocyclichydrocarbyl, wherein each heterocyclic hydrocarbyl independentlycontains one or more heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur, and further wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclic hydrocarbyl, andheterocyclic hydrocarbyl is optionally and independently substituted;each R₃₂ is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein eachheterocyclic hydrocarbyl independently contains one or more heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, and further wherein each C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionallyand independently substituted; a is 0, 1, 2, 3, 4, or 5; b is 0, 1, 2,or 3; c is an integer between 0 and 30; d is 0, 1, 2, 3, 4, 5, 6, 7, 8,or 9; e is 2; f is 2; and g is 4; wherein the optional substituents areindependently selected from the group consisting of F, Cl, Br, I, CN,C₁₋₆ halohydrocarbyl, C(O)H, C(O)C₁₋₆ hydrocarbyl, NH₂, NH(C₁₋₆hydrocarbyl), N(C₁₋₆ hydrocarbyl)₂, OH, O (C₁₋₆ hydrocarbyl), andS(O)₂C₁₋₆ hydrocarbyl.
 12. The compound according to claim 11, or apharmaceutically acceptable salt thereof, wherein, (i) A is absent; W isX₂C(═O)X₃, wherein X₂ is NR₁₈ and X₃ is absent; Y is (CR₂₂R₂₃)_(h),wherein R₂₂, R₂₃ is each independently selected from H, hydroxyl, andC₁₋₄ hydrocarbyl, h is an integer between 1 and 6; Z is (CR₂₄R₂₅)_(i),wherein R₂₄, R₂₅ is each independently selected from H, hydroxy, C₁₋₄hydrocarbyl, i is an integer between 1 and 6; c is 0; and furtherwherein each C₁₋₄ hydrocarbyl is optionally and independentlysubstituted; (ii) A is absent; W is absent or O; Y is (CR₂₂R₂₃)_(h),wherein R₂₂, R₂₃ is each independently selected from H, hydroxyl, andC₁₋₄ hydrocarbyl, h is an integer between 0 and 3; B is O; Z is(CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ is each independently selected from H,hydroxy, C₁₋₄ hydrocarbyl, i is an integer between 1 and 3; c is aninteger between 1 and 6; and further wherein each C₁₋₄ hydrocarbyl isoptionally and independently substituted; (iii) A is absent; W is NR₁₇;wherein R₁₇ is H, or C₁₋₄ hydrocarbyl; Y is (CR₂₂R₂₃)_(h), wherein R₂₂,R₂₃ is each independently selected from H, hydroxyl, and C₁₋₄hydrocarbyl, h is an integer between 0 and 3; Z is (CR₂₄R₂₅)_(i),wherein R₂₄, R₂₅ is each independently selected from H, hydroxy, andC₁₋₄ hydrocarbyl, i is an integer between 1 and 4; B is O; c is aninteger between 1 and 6; and further wherein each C₁₋₄ hydrocarbyl isoptionally and independently substituted; or (iv) A is absent; W isabsent; Y is (CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independentlyselected from H, hydroxyl, and C₁₋₄ hydrocarbyl, h is an integer between0 and 3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ is each independentlyselected from H, hydroxy, and C₁₋₄ hydrocarbyl, i is an integer between0 and 3; B is O; c is an integer between 1 and 10; and further whereineach C₁₋₄ hydrocarbyl is optionally and independently substituted. 13.The compound according to claim 11, wherein, in formula I, X is C(═O).14. The compound according to claim 11, wherein, R₁ is selected from H,and C₁₋₄ alkyl; and further wherein the C₁₋₄ alkyl is optionally andindependently substituted.
 15. The compound according to claim 11, or apharmaceutically acceptable salt thereof, wherein, R₄ is selected fromH, cyano, and C₁₋₆ alkyl; and further wherein the C₁₋₆ alkyl isoptionally and independently substituted.
 16. The compound according toclaim 11, wherein the compound is selected from the group consisting of:Compound No. Structure  3

10

13

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

39

40

41

43

and 44

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecompound according to claim
 11. 18. A medicament for treatment of adisease related to activity or expression level of Bruton's tyrosineprotein kinase (Btk), comprising the compound according to claim
 11. 19.A method for modulating Bruton's tyrosine kinase activity in a subject,comprising administering to the subject in need thereof atherapeutically effective amount of the compound according to claim 11.20. The method according to claim 19, wherein the subject has anautoimmune disease or a tumor.
 21. The method according to claim 20,wherein the autoimmune disease is selected from the group consisting ofpsoriasis and rheumatoid arthritis.
 22. The method according to claim20, wherein the tumor is related to a disease selected from the groupconsisting of B-cell lymphoma, chronic lymphocytic leukemia, andnon-Hodgkin's lymphoma.
 23. A method for inhibiting tumor cellproliferation in vitro, comprising contacting the tumor cell with thecompound according to claim
 11. 24. The method according to claim 23,wherein the tumor cell is related to a disease selected from the groupconsisting of B-cell lymphoma, chronic lymphocytic leukemia, andnon-Hodgkin's lymphoma.